Highly active antiretroviral therapy (HAART) has resulted in improved longevity in HIV-infected patients and a growing prevalence of HIV infection in people over the age of 50. Some preliminary data suggest that older patients may not respond as well to HAART as younger patients. Specifically, immune recovery may be less good, and both morbidity and mortality rates may be higher in older patients. As the HIV-infected population ages, there is a growing need to better define the natural history of the disease, the effectiveness of therapy, and the effect of age-related comorbidities on disease progression. We propose to conduct an observationalcohort study of 3,600 HIV-infected individuals (1,800 aged 50 years and over and 1,800 under age 50 years, matched on year of HAART initiation, pre-HAART CD4, and site of care) followed at 5 HIV primary care sites in the United States. Specific aim 1: evaluate virologic and immunologic response, HIV disease progression, and mortality in patients over 50 on HAART compared to younger patients on HAART. We hypothesize that older patients will achieve greater rates of virologic suppression, but less immunologic response and have worse HIV disease progression and mortality than younger patients. Our primary study outcome will be HIV disease progression. Secondary outcomes will include changes in CD4+ cell counts, viral load suppression, and death. Specific Aim 2: evaluate the incidence of adverse drug reactions (ADRs), particularly hepatotoxicity, nephrotoxicity, pancreatitis, diabetes, and lipid abnormalities in older HIV-infected patients, stratified by HAART class. We hypothesize that older patients on PI based HAART will have more ADR's requiring cessation of HAART than HIV+ older patients on NNRTI based HAART. Specific Aim 3: define incidence, prevalence, and mortality from comorbidities in HIV-infected patients over age 50 with a particular focus on (a) end-stage renal disease, (b) non-HIV related malignancies, (c) anemia and (d) cardiovascular disease. We hypothesize that older patients will have a greater incidence of these comorbidities than age matched HIV seronegative controls. Our primary outcomes will be incidence and prevalence of these comorbidities. Secondary outcomes will include cause-specific mortality. Our research team has an established history of collaboration in HIV and aging, and brings together a wealth of research expertise in HIV treatment outcomes, co-morbidities in the elderly, and novel biostatistical and epidemiological methodologies in cohort studies and longitudinal analyses of HIV disease and AIDS.